Samenvatting
In the present thesis work, the general aim was to identify predictive molecular markers for clinical pregnancy in stimulated IVF cycles with embryo transfer.In the first part of this study (Van Vaerenbergh et al., 2009), the molecular profiles of endometrial biopsies were studied in relation to the histological maturation state of the endometrium on the day of oocyte retrieval. A distinct molecular profile, with several involved pathways and networks, and two clusters were discovered when patients with an endometrial advanced secretory maturation of 2 or 3 days and patients with an endometrial biopsy more than 3 days advanced were compared.
These new 'molecular dating' results support the results of the more classical histological dating of the biopsy according to Noyes' criteria. In two former studies with endometrial biopsies on the day of oocyte retrieval followed by embryo replacement (Ubaldi et al., 1997; Kolibianakis et al., 2002), no pregnancies ensued in patients with a histological dating result on the day of oocyte retrieval exceeding 3 days advancement. Therefore, the present gene expression data appear to indicate that such an analysis is able to identify a clearly separated subgroup of patients where IVF treatment will not lead to a clinical pregnancy, apparently due to a lower endometrial receptivity.
In the second part of this study (Van Vaerenbergh et al., 2011), a comparison was made between pregnant and non-pregnant patients on the day of oocyte retrieval in two different GnRH-antagonist stimulation protocols for IVF. The present data suggest that increased gene expression of COX-2, together with expression of other molecules in the COX-2 network, on the day of oocyte retrieval in GnRH-antagonist cycles for IVF coincides with a lower probability of achieving a clinical pregnancy in this cycle.
In some patients for IVF in stimulated cycles, a rise in serum progesterone levels towards the end of the follicular phase can be detected. Currently, there is a lot of debate about this issue and its effect on pregnancy rates.
Therefore, the gene expression between patient groups with different progesterone levels on the day of hCG administration was assessed in the third part of this study (Van Vaerenbergh et al., 2010 b). In this way, we want to test the arbitrary threshold for progesterone serum levels.
Patients were divided into three groups according to their P serum concentration on the day of hCG administration: (A) P 1.5 ng/ml. Endometrial gene expression analysis showed a small number of significantly differentially expressed probe sets between the groups with P 1.5 ng/ml. This is the first study to demonstrate a distinct difference in endometrial gene expression profile between patients with a P serum level above and below the threshold of 1.5 ng/ml on the day of hCG administration, which might reflect an important issue for implantation failure in IVF patients with premature progesterone rise.
Gene expression was studied as well on an endometrial biopsy taken during the window of implantation and the implantation of a human embryo in a natural cycle (Van Vaerenbergh et al., 2010 a). This patient became pregnant in this cycle and gave birth to a healthy baby. As such, this was a unique model to study the cross-talk between the implanting embryo and the receptive endometrium. Different active networks and pathways involved during the implantation process were established. One pathway, the ephrin signalling pathway, was studied closer and four genes were validated on the protein level with immunohistochemistry in this pathway.
Together, this shows that the implantation process, studied in a natural cycle, is a complex process with many pathways and networks involved, which are regulated differently from those on the moment of oocyte retrieval in stimulated cycles for IVF.
Taken together, the gene expression data in the studies in stimulated IVF cycles indicate that variations in endometrial maturation and progesterone concentrations on the day of hCG administration have an effect on endometrial gene expression. These events may be related to each other as the premature progesterone rise may have an effect on the maturation state of the endometrium, and thus on pregnancy outcome. From this study, the same gene marker was found in two stimulation protocols for IVF in the comparison between pregnant and non-pregnant patients. Therefore, if more patients could be analysed, a clinical applicable predictive molecular clustering tool or molecular gene marker(s) for a receptive endometrium can be developed.
This study points towards a genetic signature for a receptive endometrium in stimulated cycles for IVF.
| Datum prijs | 10 mei 2011 |
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| Originele taal | English |
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| Begeleider | Claire Bourgain (Promotor), Pieter in 't Veld (Co-promotor), Paul Devroey (Co-promotor), Brigitte Velkeniers-Hoebanckx (Jury), Johan Smitz (Jury), Hilde Van De Velde (Jury), N.s. Macklon (Jury), José Horcajadas (Jury) & S Perrier D'hauterive (Jury) |